Fatty liver, also named hepatic steatosis, is defined as an excessive accumulation of fat in hepatocytes (Bravo A A, et al. N. Engl. J. Med. 2001:344; 495-500; Angulo P. N. Engl. J. Med. 2002 Apr. 18; 346(16):1221-31). Fatty liver disease involves the accumulation of triglycerides in hepatocytes, necrosis of hepatocytes, inflammation (Day C P. Best Pract. Res. Clin. Gastroenterol. 2002; 16:663-78; Browning J D, Horton J D. J. Clin. Invest. 2004; 114:147-52), small hepatic veins obliteration and often fibrosis with sometimes progression to cirrhosis, hepatocellular cancer and liver-related death (El-Serag H B, et al. Gastroenterology 2004; 126:460-468, Dam-Larsen S, et al. Gut 2004; 53:750-5).
Worldwide the prevalence of hepatic steatosis is very high, associated with several factors such as alcohol, diabetes, overweight, hyperlipidemia, insulin resistance, hepatitis C genotype 3, abetalipoproteinemia and some drugs (Bellentani S, et al. Ann. Intern. Med. 2000; 132:112-7; Levitsky J, Mailliard M E. Semin. Liver Dis. 2004; 24:233-47).
Non-alcoholic fatty liver disease (NAFLD), is an adaptive response of the liver to insulin resistance that can trigger non-alcoholic steatohepatitis (NASH), which can itself induce a fibrogenic response that can result in cirrhosis (Day C P. Best Pract. Res. Clin. Gastroenterol. 2002; 16:663-78).
In patients with alcoholic liver disease (Sorensen T I, et al. Lancet. 1984; 2:241-4), chronic hepatitis C (Fabris P, et al. J. Hepatol. 2004; 41:644-51), and perhaps in hepatitis B (Phillips M J, et al. Am. J. Pathol. 1992; 140:1295-308), the presence of hepatic steatosis is also associated with fibrosis progression, with or without associated necroinflammatory lesions (alcoholic or viral hepatitis).
There is no standard recommendation for the diagnosis of hepatic steatosis. The usual recommendation is to measure GGT and ALT and to perform liver biopsy for the grading and staging (Bellentani S, et al. Ann. Intern. Med. 2000; 132:112-7; Levitsky J, Mailliard M E. Semin. Liver Dis. 2004; 24:233-47; Bravo A A, et al. N. Engl. J. Med. 2001:344; 495-500). As liver biopsy is still an invasive and costly procedure, with a potential sampling error, it could be advantageous to have a fast and easy to perform test that would give a good predictive value of the level of hepatic steatosis in the patient.
For the diagnosis of fibrosis, non-invasive FibroTest (FT) (Biopredictive, Paris France, U.S. Pat. No. 6,631,330) has been validated as surrogate marker in chronic hepatitis C (Poynard T, et al. Comp Hepatol. 2004; 3:8) and B (Myers R P, et al. J Hepatol. 2003; 39:222-30) and recently in alcoholic liver disease (Callewaert N, et al. Nature Med 2004; 10; 1-6; Naveau S, et al. Clin Gastroenterol Hepatol in press).
So far, however, no study has demonstrated that a single or a panel of biomarkers can be used as an alternative to liver biopsy for the diagnosis of hepatic steatosis in the most common causes: alcohol, viral hepatitis and NAFLD.
There is therefore a need to develop a diagnosis method that would give a good predictive value of the extent of hepatic steatosis in a patient, and that would be reliable enough to reduce the need of liver biopsy. This method would be particularly advantageous for a patient who suffers from a disease involving hepatic steatosis or who already had a positive diagnostic test of liver fibrosis or necroinflammatory lesions, to adapt the treatment to his precise disease.